Previous studies on lead have typically analyzed covariate markers of social stress as independent predictors of neurodevelopment, considering them potential confounders. There are biological reasons to believe that psychosocial stress potentiates the toxicity of lead. If so, then understanding this relationship may be the key to designing effective public health interventions designed to improve neurodevelopment in children. The ELEMENT cohort has created the infrastructure for such a study and is uniquely positioned to address these important neurotoxicological questions. In this competing renewal, we hypothesize that lead exposure and social stressors experienced jointly in pregnancy and infancy will have multiplicatively increased deleterious effects on neurodevelopment (i.e. environment X environment interactions). Based on work conducted by others in animals, this should result in selective impairments in memory (hippocampus) and fixed interval responses (nucleus accumbens) due to the established vulnerability of these structures to stress and lead. Our results thus far have established a consistent pattern of adverse effects to both lead and social stress, as well as disturbed salivary cortisol rhythms following high levels of stress. We also find multiplicative changes in cortisol rhythms when these exposures occur in the context of high lead exposure. Cortisol may thus represent a mechanistic link between lead and stress. We have already enrolled 1000 infants in Mexico City measuring stress and lead exposure longitudinally beginning in the 2nd trimester through age 2 years. To date, we have measured only infant development via Bayley Scales. In this renewal we propose to measure more detailed neurophenotypes as the children age (behavior, cognition, memory) as well as tests specific to hippocampal and nucleus accumbens function. Social and educational interventions, if targeted properly, could be effective treatments. This research will identify those interventions. PUBLIC HEALTH RELEVANCE: This study will examine the effects of perinatal exposure to psychosocial stressors (violence, perceived stress, depression) on childhood neurobehavioral and cognitive development in school age children. In addition to independent effects of stress, the study will also examine the potential modifying effects of the social environment (i.e., psychological stress) on lead toxicity. Such knowledge may inform efforts to design programs that improve neurodevelopmental trajectories in high-risk disadvantaged populations disproportionately exposed to adverse physical and social environments.